Relationship of fibrinolysis system proteins with severity of COVID-19. A review of current clinical data and promising therapeutic strategies

Modern clinical studies show the association of fibrinolysis system factors with complications following COVID-19. This review includes the studies describing the relationship of urokinase plasminogen activator proteins uPA and its receptor uPAR, plasmin-ogen activator inhibitor PAI-1 and plasmin itself with severity of COVID-19. Potential of diagnosis based on analysis of concen-trations and activities of these proteins, as well as expression of their encoding genes is described. These data can predict severe course and possible complications of COVID-19 including thrombosis, respiratory failure and cytokine storm. © 2022, Media Sphera Publishing Group. All rights reserved.

Androgen deprivation therapy and hormonal status in men with COVID-19.

Severe course of cOVID-19 among men compared to the female led to a detailed study of the hormonal status of men with cOVID-19. The earliest works about this focused on the incidence and severity of cOVID-19 depending on the intake of androgen deprivation therapy. At the same time, different classes of androgen deprivation therapy have different effects on androgen concentration that was not always considered in the analysis. In this regard, we conducted a review of the available literature data with a targeted study of works that included androgen deprivation therapy with a unidirectional effect on the concentration of male sex hormones. In addition, we conducted a review of studies focused on the relationship between cOVID-19 and androgens (testosterone and dihydrotestosterone).Copyright © 2022 Authors. All rights reserved.

Proactive anti-inflammatory therapy in the advanced stages of a new coronavirus infection. Main results of the inpatient phase of the COLORIT study (Colchicin vs. Ruxolitinib and secukinumab in an open, prospective, randomized trial in patients with novel coronavirus infection COVID-19).

Aim      To evaluate clinical efficacy of the proactive anti-inflammatory therapy in patients hospitalized for COVID-19 with pneumonia and a risk of "cytokine storm".Material and methods  The COLORIT study was a comparative study with randomization into 4 groups: colchicine (n=21) 1 mg for the first 3 days followed by 0.5 mg/day through day 12 or discharge from the hospital; secukinumab 300 mg/day, s.c., as a single dose (n=20); ruxolitinib 5 mg, twice a day (n=10); and a control group with no anti-inflammatory therapy (n=22). The effect was evaluated after 12±2 days of inpatient treatment or upon discharge, what comes first. For ethical reasons, completely randomized recruitment to the control group was not possible. Thus, for data analysis, 17 patients who did not receive any anti-inflammatory therapy for various reasons not related with inclusion into the study were added to the control group of 5 randomized patients. Inclusion criteria: presence of coronavirus pneumonia (positive PCR test for SARS-CoV-2 RNA or specific clinical presentation of pneumonia; IDC-10 codes U07.1 and U07.2); C-reactive protein (CRP) concentration >60 mg/l or its threefold increase from baseline; at least 2 of 4 symptoms (fever >37.5 °C, persistent cough, shortness of breath with inspiratory rate >20 per min or blood saturation with oxygen <94 % by the 7th-9th day of disease. The study primary endpoint was changes in COVID Clinical Condition Scale (CCS-COVID) score. The secondary endpoints were the dynamics of CRP and changes in the area of lung lesion according to data of computed tomography (CT) of the lungs from the date of randomization to 12±2 days.Results All three drugs significantly reduced inflammation, improved the clinical course of the disease, and decreased the disease severity as evaluated by the CCS score: in the ruxolitinib group, by 5.5 (p=0.004); in the secukinumab group, by 4 (p=0.096); in the colchicine group, by 4 (p=0.017), and in the control group, by 2 (р=0.329). In all three groups, the CCS-COVID score was 2-3 by the end of observation period, which corresponded to a mild process, while in the control group, the score was 7 (р=0.005). Time-related changes in CRP were significant in all three anti-inflammatory treatment groups with no statistical difference between the groups. By the end of the study, changes in CT of the lungs were nonsignificant.Conclusion      In severe СOVID-19 with a risk of "cytokine storm", the proactive therapy with ruxolitinib, colchicine, and secukinumab significantly reduces the inflammation severity, prevents the disease progression, and results in clinical improvement.

The Burden of Residual SymptOms That Complicate the Life of Patients Who Have Suffered a new Coronavirus Infection (THROW study).

Aim      To evaluate the prevalence of residual symptoms in patients hospitalized for novel coronavirus infection at 8 months after discharge and the severity of such symptoms depending on demographic characteristics, concurrent diseases, and specific features of the acute period of COVID-19.Material and methods  This study included the patients who were managed for novel coronavirus infection in a COVID-19 hospital and provided their consent to participate in the study (98 patients). At 8 months after discharge from the hospital, a structured telephone interview was performed.Results Only 40 % of patients treated for COVID-19 did not have any complaints at 8 months after discharge from the hospital. The most frequent complaints in the long term were fatigue (30.5 %), weakness (28.4 %), shortness of breath (23.2 %), arthralgia (22.1 %), myalgia (17.9 %), and anosmia (15.8 %). The background of chronic diseases and obesity, percentage of lung damage according to CT data, and the requirement for oxygen support during the acute period in our sample were not related with the presence of symptoms in the long term. The presence and severity of symptoms during the long term were not determined by the clinical condition, volume of lung damage, or requirement for oxygen support but were related with the gender and severity of inflammation upon admission.Conclusion      Independent predictors for persistence of symptoms in the patient sample with severe novel coronavirus infection during the long term included chest and joint pain during the stay in the hospital, female gender, and increased levels of C-reactive protein upon admission.

Androgen deprivation therapy and hormonal status in men with COVID-19

Severe course of cOVID-19 among men compared to the female led to a detailed study of the hormonal status of men with cOVID-19. The earliest works about this focused on the incidence and severity of cOVID-19 depending on the intake of androgen deprivation therapy. At the same time, different classes of androgen deprivation therapy have different effects on androgen concentration that was not always considered in the analysis. In this regard, we conducted a review of the available literature data with a targeted study of works that included androgen deprivation therapy with a unidirectional effect on the concentration of male sex hormones. In addition, we conducted a review of studies focused on the relationship between cOVID-19 and androgens (testosterone and dihydrotestosterone).

Relationship of fibrinolysis system proteins with severity of COVID-19. A review of current clinical data and promising therapeutic strategies

Modern clinical studies show the association of fibrinolysis system factors with complications following COVID-19. This review includes the studies describing the relationship of urokinase plasminogen activator proteins uPA and its receptor uPAR, plasmin-ogen activator inhibitor PAI-1 and plasmin itself with severity of COVID-19. Potential of diagnosis based on analysis of concen-trations and activities of these proteins, as well as expression of their encoding genes is described. These data can predict severe course and possible complications of COVID-19 including thrombosis, respiratory failure and cytokine storm. © 2022, Media Sphera Publishing Group. All rights reserved.

PROTECTIVE POTENTIAL OF 5-ALPHA-REDUCTASE INHIBITORS ON COVID-19 INCIDENCE AND SEVERITY: RESULTS FROM RETROSPECTIVE COHORT STUDY FOUNDER (FEATURES OF A NEW CORONAVIRUS INFECTION COURSE AND OPTIONS THERAPY DEPENDING ON THE ANDROGENIC STATUS)

Purpose. Assessment of COVID-19 incidence and hospitalization rate of male patients with prostatic hyperplasia depending on the intake of 5-alpha-reductase inhibitors (5-ARI). Materials and methods. In our study, electronic medical records of 1678 patients with prostatic hyperplasia were analyzed. 1490 men aged 71 (64-76) years were selected for final analysis. Vaccination against COVID-19 was carried out in 730 patients (49%). Treatment with 5-ARI inhibitors was carried out in 269 (18.1%) patients. Results. Among 1490 included patients 790 (53%) had COVID-19 while 360 (45.7%) of them required hospitalization. During the multivariate analysis, only two factors were associated with the risk of COVID-19 in the cohort studied: vaccination (odds ratio (OR) =0.095;95% confidence interval (CI) 0.074-0.122), i.e. a 90.5% chance reduction, p<0.001) and the fact of taking 5-ARI (OR=0.235;95%CI=0.165-0.335;p<0.001), i.e. a 76.5% chance reduction. The duration of 5-ARI therapy was not associated with the incidence of new coronavirus infection. The severe course of COVID-19 which required hospitalization was positively associated with age (p=0.025) and the presence of coronary artery disease (p=0.004);and negatively associated with the frequency of vaccination (p<0.001) and treatment of 5-ARI (3.1% vs. 11.6%, p<0.001). In a multivariate analysis of outpatient patients with prostatic hyperplasia who had COVID-19, 5-ARI intake (OR=0.240;95% CI 0.122-0.473;p<0.001) and vaccination (OR = 0.570;95% CI 0.401-0.808;p=0.002). The factors associated with increased chances of hospitalization due to the severe course of COVID-19 were coronary heart disease (+43.8%, p=0.019) and older age (+1.7% by one year, p=0.046). Conclusion. Taking 5-ARI, along with vaccination in patients with prostatic hyperplasia is a protective factor for morbidity and the severity of COVID-19. © 2022, Bionika Media Ltd. All rights reserved.

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PURPOSE: Assessment of COVID-19 incidence and hospitalization rate of male patients with prostatic hyperplasia depending on the intake of 5-alpha-reductase inhibitors (5-ARI). MATERIALS AND METHODS: In our study, electronic medical records of 1678 patients with prostatic hyperplasia were analyzed. 1490 men aged 71 (64-76) years were selected for final analysis. Vaccination against COVID-19 was carried out in 730 patients (49%). Treatment with 5-ARI inhibitors was carried out in 269 (18.1%) patients. RESULTS: Among 1490 included patients 790 (53%) had COVID- 19 while 360 (45.7%) of them required hospitalization. During the multivariate analysis, only two factors were associated with the risk of COVID-19 in the cohort studied: vaccination (odds ratio (OR) =0.095;95% confidence interval (CI) 0.074-0.122), i.e. a 90.5% chance reduction, p<0.001) and the fact of taking 5-ARI (OR=0.235;95%CI=0.165-0.335;p<0.001), i.e. a 76.5% chance reduction. The duration of 5-ARI therapy was not associated with the incidence of new coronavirus infection. The severe course of COVID-19 which required hospitalization was positively associated with age (p=0.025) and the presence of coronary artery disease (p=0.004);and negatively associated with the frequency of vaccination (p<0.001) and treatment of 5-ARI (3.1% vs. 11.6%, p<0.001). In a multivariate analysis of outpatient patients with prostatic hyperplasia who had COVID-19, 5-ARI intake (OR=0.240;95% CI 0.122-0.473;p<0.001) and vaccination (OR = 0.570;95% CI 0.401-0.808;p=0.002). The factors associated with increased chances of hospitalization due to the severe course of COVID-19 were coronary heart disease (+43.8%, p=0.019) and older age (+1.7% by one year, p=0.046). CONCLUSION: Taking 5-ARI, along with vaccination in patients with prostatic hyperplasia is a protective factor for morbidity and the severity of COVID-19.

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PURPOSE: Assessment of COVID-19 incidence and hospitalization rate of male patients with prostatic hyperplasia depending on the intake of 5-alpha-reductase inhibitors (5-ARI).

[Features of a new corOnavirUs infection course and optioNs therapy DEpending on the andRogenic status (FOUNDER): androgenic status in men with COVID-19 and its relationship with the disease severity]

OBJECTIVE: Analysis of androgen status in men hospitalized with a moderate COVID-19 and its relationship with the severity of the disease. MATERIALS AND METHODS: The study included 152 males with a confirmed diagnosis of COVID-19 based on the results of a positive PCR for the SARS-CoV-2 virus and/or computed tomography of the lungs hospitalized at the MSU University Clinic due to the moderate and severe COVID-19. Examination of the level of biochemical blood parameters (CRP, creatinine, urea, glucose, total testosterone (T));CT of the lungs. To objectify the severity of the clinical symptoms, the NEWS2 distress syndrome severity scales and the original scale for assessing the clinical condition of patients with COVID 19 (SHOCS-COVID) were used. RESULTS: The median T level in 152 examined patients was 2.14 [1.21;3.40] ng/ml. In patients with a T level below the median, the CRP level was more than two times higher, and the D-dimer value was almost two times higher than in patients with T level above median. The duration of treatment in the hospital was longer in men with COVID 19 and an initial T level below the median than in patients with T about the median (13 days vs 10.5 days, p=0.003). Low T level was correlated with lung damage by lung CT. After improving the clinical condition, there was a linear increase in the level of T independent of its initial level. CONCLUSION: Among men with moderate and severe COVID-19, a decreased testosterone level is detected in 46.7% of cases. Patients with low testosterone levels on admission have more severe COVID-19. A significant increase in testosterone level was observed after successful COVID-19 treatment without any special action regarding testosterone level.

Possible role of anti-IL17 drugs in the management of COVID-19: Our own experience and literature review

Coronavirus infection COVID-19 is an acute respiratory viral disease caused by a novel beta-coronavirus SARS-CoV-2. In 81 % of cases, mortality in COVID-19 patients is associated with the development of acute respiratory distress syndrome (ARDS). Another critical challenge associated with COVID-19 is the development of a cytokine storm, which is an uncontrolled release of proinflammatory mediators due to the excessive activation of immune system. Cytokine storm is another cause of high mortality because of COVID-19, as it leads to multiple organ failure, ARDS and disseminated intravascular coagulation (DIC). Thus, the management of cytokine storm and ARDS in COVID-19 patients is an urgent issue for the medical society. Recent research assessed the potential role of interleukin(IL)-17 in the pathogenesis of cytokine storm and ARDS in COVID-19 patients. Some authors also pointed to using anti-IL17 medications in the management of patients with severe COVID-19. The present article gives a literature review on the possible role of IL-17 in COVID-19 pathogenesis and our personal experience of anti-IL17 prescription for patients with severe course of COVID-19.

Hydroxychloroquine in patients with novel coronavirus infection (COVID-19): a case-control study.

Actuality One of the most widely discussed treatments for patients with COVID-19, especially at the beginning of the epidemy, was the use of the antimalarial drug hydroxychloroquine (HCQ). The first small non-randomized trials showed the ability of HCQ and its combination with azithromycin to accelerate the elimination of the virus and ease the acute phase of the disease. Later, large, randomized trials did not confirm it (RECOVERY, SOLIDARITY). This study is a case-control study in which we compared patients who received and did not receive HCQ.Material and Methods 103 patients (25 in the HCQ treatment group and 78 in the control group) with confirmed COVID-19 (SARS-CoV-2 virus RNA was detected in 26 of 73 in the control group (35.6%) and in 10 of 25 (40%) in the HCQ group) and in the rest - a typical picture of viral pneumonia on multislice computed tomography [MSCT]) were included in the analysis. The severity of lung damage was limited to stages I-II, the CRP level should not exceed 60 mg/dL, and oxygen saturation in the air within 92-98%. We planned to analysis the duration of treatment of patients in the hospital, the days until the normalization of body temperature, the number of points according to the original SHOCS-COVID integral scale, and changes in its components (C-reactive protein (CRP), D-dimer, and the percentage of lung damage according to MSCT).Results Analysis for the whole group revealed a statistically significant increase in the time to normalization of body temperature from 4 to 7 days (by 3 days, p<0.001), and the duration of hospitalization from 9.4 to 11.8 days (by 2.4 days, p=0.002) when using HCQ in comparison with control. Given the incomplete balance of the groups, the main analysis included 46 patients who were matched by propensity score matching. The trend towards similar dynamics continued. HCQ treatment slowed down the time to normalization of body temperature by 1.8 days (p=0.074) and lengthened the hospitalization time by 2.1 days (p=0.042). The decrease in scores on the SHOCS -COVID scale was statistically significant in both groups, and there were no differences between them (delta - 3.00 (2.90) in the HCQ group and - 2.69 (1.55) in control, p=0.718). At the same time, in the control group, the CRP level returned to normal (4.06 mg/dl), and with the use of GC, it decreased but remained above the norm (6.21 mg/dl, p=0.05). Side effects requiring discontinuation of treatment were reported in 3 patients in the HCQ group and none in the control group.Conclusion We have not identified any positive properties of HCQ and its ability to influence the severity of COVID-19. This antimalarial agent slows down the normalization of the body's inflammatory response and lengthens the time spent in the hospital. HCQ should not be used in the treatment of COVID-19.

[Combination therapy at an early stage of the novel coronavirus infection (COVID-19). Case series and design of the clinical trial "BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT)"].

The article focuses on effective treatment of the novel coronavirus infection (COVID-19) at early stages and substantiates the requirement for antiviral therapy and for decreasing the viral load to prevent the infection progression. The absence of a specific antiviral therapy for the SARS-CoV-2 virus is stated. The authors analyzed results of early randomized studies using lopinavir/ritonavir, remdesivir, and favipiravir in COVID-19 and their potential for the treatment of novel coronavirus infection. Among the drugs blocking the virus entry into cells, the greatest attention was paid to the antimalaria drugs, chloroquine and hydroxychloroquine. The article addresses in detail ineffectiveness and potential danger of hydroxychloroquine, which demonstrated neither a decrease in the time of clinical recovery nor any improvement of prognosis for patients with COVID-19. The major objective was substantiating a possible use of bromhexine, a mucolytic and anticough drug, which can inhibit transmembrane serin protease 2 required for entry of the SARS-CoV-2 virus into cells. Spironolactone may have a similar feature. Due to its antiandrogenic effects, spironolactone can inhibit X-chromosome-related synthesis of ACE-2 receptors and activation of transmembrane serin protease 2. In addition to slowing the virus entry into cells, spironolactone decreases severity of fibrosis in different organs, including the lungs. The major part of the article addresses clinical examples of managing patients with COVID-19 at the University Clinic of the Medical Research and Educational Centre of the M. V. Lomonosov Moscow State University, including successful treatment with schemes containing bromhexine and spironolactone. In conclusion, the authors described the design of a randomized, prospective BISCUIT study performed at the University Clinic of the M. V. Lomonosov Moscow State University with an objective of evaluating the efficacy of this scheme.

[Steroid pulse -therapy in patients With coronAvirus Pneumonia (COVID-19), sYstemic inFlammation And Risk of vEnous thRombosis and thromboembolism (WAYFARER Study)].

Introduction Coronavirus pneumonia not only severely affects the lung tissue but is also associated with systemic autoimmune inflammation, rapid overactivation of cytokines and chemokines known as "cytokine storm", and a high risk of thrombosis and thromboembolism. Since there is no specific therapy for this new coronavirus infection (COVID-19), searching for an effective and safe anti-inflammatory therapy is critical.Materials and methods This study evaluated efficacy and safety of pulse therapy with high doses of glucocorticosteroids (GCS), methylprednisolone 1,000 mg for 3 days plus dexamethasone 8 mg for another 3-5 days, in 17 patients with severe coronavirus pneumonia as a part of retrospective comparative analysis (17 patients in control group). The study primary endpoint was the aggregate dynamics of patients' condition as evaluated by an original CCS-COVID scale, which included, in addition to the clinical status, assessments of changes in the inflammation marker, C-reactive protein (CRP); the thrombus formation marker, D-dimer; and the extent of lung injury evaluated by computed tomography (CT). Patients had signs of lung injury (53.2 % and 25.6 %), increases in CRP 27 and 19 times, and a more than doubled level of D-dimer (to 1.41 µg/ml and 1.15 µg/ml) in the active therapy and the control groups, respectively. The GCS treatment group had a more severe condition at baseline.Results The GCS pulse therapy proved effective and significantly decreased the CCS-COVID scores. Median score difference was 5.00 compared to the control group (р=0.011). Shortness of breath considerably decreased; oxygen saturation increased, and the NEWS-2 clinical status scale scores decreased. In the GCS group, concentration of CRP significantly decreased from 134 mg/dl to 41.8 mg/dl (р=0.009) but at the same time, D-dimer level significantly increased from 1.41 µg/ml to 1.98 µg/ml (р=0.044). In the control group, the changes were nonsignificant. The dynamics of lung injury by CT was better in the treatment group but the difference did not reach a statistical significance (р=0.062). Following the GCS treatment, neutrophilia increased (р=0.0001) with persisting lymphopenia, and the neutrophil/lymphocyte (N/L) ratio, a marker of chronic inflammation, increased 2.5 times (р=0.006). The changes in the N/L ratio and D-dimer were found to correlate in the GCS pulse therapy group (r =0.49, p=0.04), which underlined the relationship of chronic autoimmune inflammation with thrombus formation in COVID-19. No significant changes were observed in the control group. In result, four patients developed venous thromboembolic complications (two of them had pulmonary artery thromboembolism) after the GCS pulse therapy despite the concomitant antiplatelet treatment at therapeutic doses. Recovery was slower in the hormone treatment group (median stay in the hospital was 26 days vs 18 days in the control group, р=0.001).Conclusion Pulse therapy with high doses of GCS exerted a rapid anti-inflammatory effect but at the same time, increased the N/L ratio and the D-dimer level, which increased the risk of thromboembolism.